EP3700514B1 - Kombination von il-8-inhibitoren und il-6/gp-130-inhibitoren zur behandlung von lungenmetastasen in verbindung mit osteosarkomen - Google Patents

Kombination von il-8-inhibitoren und il-6/gp-130-inhibitoren zur behandlung von lungenmetastasen in verbindung mit osteosarkomen Download PDF

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EP3700514B1
EP3700514B1 EP18795414.4A EP18795414A EP3700514B1 EP 3700514 B1 EP3700514 B1 EP 3700514B1 EP 18795414 A EP18795414 A EP 18795414A EP 3700514 B1 EP3700514 B1 EP 3700514B1
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inhibitor
alkyl
linear
branched
kit
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EP3700514A1 (de
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Ryan David ROBERTS
Laura Brandolini
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Dompe Farmaceutici SpA
Nationwide Childrens Hospital Inc
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Dompe Farmaceutici SpA
Nationwide Childrens Hospital Inc
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Priority to EP24221501.0A priority Critical patent/EP4548916A1/de
Priority to SM20250202T priority patent/SMT202500202T1/it
Priority to SI201831238T priority patent/SI3700514T1/sl
Priority to RS20250531A priority patent/RS66852B1/sr
Priority to HRP20250641TT priority patent/HRP20250641T1/hr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
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    • A—HUMAN NECESSITIES
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    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a product or kit for use in the prevention and/or treatment of lung metastasis associated to osteosarcoma, the product or kit comprising: A) an IL-8 inhibitor, and B) at least one IL-6 inhibitor and/or at least one gp130 inhibitor, A) and B) being two separate formulations for simultaneous, separate or sequential use.
  • the invention also relates to a pharmaceutical composition for use in the prevention and/or treatment of lung metastasis associated to osteosarcoma, comprising an IL-8 inhibitor and pharmaceutically acceptable excipients and/or diluents, wherein the pharmaceutical composition further comprises at least one IL-6 inhibitor and/or at least one gp130 inhibitor.
  • Bone and soft tissue sarcomas are a group of rare heterogeneous forms of cancer, which collectively account for approximately 1% of all malignancies diagnosed. Sarcomas represent a challenge to clinicians as they are rare and diagnosis is often delayed.
  • Soft tissue sarcomas develop from soft tissue cells including smooth muscle cells (leiomyosarcomas), fat cells (liposarcomas), fibrous connective tissue (fibrosarcomas), skeletal muscles (rhabdomyosarcomas), synovium (synovial sarcomas), blood vessels (angiosarcomas), breast ducts (phyllodes tumours) and nerves (nerve sheath tumours).
  • Osteosarcoma is an aggressive malignant neoplasm that arises from primitive transformed cells of mesenchymal origin (and thus a sarcoma) and that exhibits osteoblastic differentiation and produces malignant osteoid.
  • a complete radical, surgical, en bloc resection of the cancer is the treatment of choice in osteosarcoma. Although about 90% of patients are able to have limb-salvage surgery, complications, particularly infection, prosthetic loosening and non-union, or local tumor recurrence may cause the need for further surgery or amputation.
  • Standard therapy is a combination of limb-salvage orthopedic surgery when possible (or amputation in some cases) and chemotherapy.
  • Ewing sarcoma is a highly aggressive bone tumor with peak incidence in the adolescent population. It has a high propensity to metastasize, which is associated with dismal survival rates of approximately 25% ( Satterfield, L. et al, Int. J. Cancer, 141: 2062-2075; 2017 ; Beverly A. Teicher et al, Ann Saudi Med., 31(2): 174-182; 2011 ).
  • EWS/FLI1 plays a dominant role in tumor progression by modulating the expression of hundreds of target genes.
  • EWS/FLI1 inhibition by RNAi-mediated knockdown, on cellular signaling was investigated using mass spectrometry-based phosphoproteomics to quantify global changes in phosphorylation.
  • This unbiased approach identified hundreds of unique phosphopeptides enriched in processes such as regulation of cell cycle and cytoskeleton organization.
  • phosphotyrosine profiling revealed a large upregulation of STAT3 phosphorylation upon EWS/FLI1 knockdown.
  • Rhabdomyosarcoma is an aggressive and highly malignant form of cancer that develops from skeletal (striated) muscle cells that have failed to fully differentiate. It is generally considered to be a disease of childhood, as the vast majority of cases occur in those below the age of 18.
  • RMS soft-tissue sarcoma
  • rhabdomyosarcoma Treatment of rhabdomyosarcoma is a multidisciplinary practice involving the use of surgery, chemotherapy, radiation, and possibly immunotherapy. Surgery is generally the first step in a combined therapeutic approach. Resectability varies depending on tumor site, and RMS often presents in sites that don't allow for full surgical resection without significant morbidity and loss of function. Less than 20% of RMS tumors are fully resected with negative margins. Fortunately, rhabdomyosarcomas are generally chemosensitive, with approximately 80% of cases responding to chemotherapy. Multi-agent chemotherapy is indicated for all patients with rhabdomyosarcoma. Before the use of adjuvant and neoadjuvant therapy involving chemotherapeutic agents, treatment solely by surgical means had a survival rate of ⁇ 20%. Modern survival rates with adjuvant therapy are approximately 60-70%.
  • Metastasis kills patients with solid tumors. Nowhere is this more evident than in osteosarcoma.
  • the deadly bone cancer osteosarcoma (OS) kills primarily through metastatic spread to lung.
  • the mechanisms driving this lung tropism remain unknown. Whether patients present with grossly metastatic disease at diagnosis or metastases arise many years after completing therapy, patients with localized disease enjoy a relatively favorable 70% 5-year overall survival rate, while those with lung metastasis suffer an abysmal 15% 2-year survival ( Allison D. C. et al; Sarcoma 2012, 704872; 2012 ).
  • a therapy which prevents the emergence of lung metastasis in children and adolescents with osteosarcoma would save the lives of more than 70% of those who currently die from their disease.
  • US2017/0165363A1 discloses methods of treating or preventing cancer in patients by administering Interleukin 6 (IL-6) inhibitor and Interleukin 8 (IL-8) inhibitor, in a concentration ratio range to inhibit the migration of cancer cells.
  • IL-6 Interleukin 6
  • IL-8 Interleukin 8
  • the compounds are tested on fibrosarcoma cells (HT1080WT).
  • Interleukin-8 (IL-8; CXCL8) is considered a major mediator of PMN (Polymorphonuclear Neutrophils) recruitment and is involved in several pathologies including psoriasis, rheumatoid arthritis, chronic obstructive pulmonary disease and reperfusion injury in transplanted organ ( Griffin et al, Arch Dermatol 1988, 124: 216 ; Fincham et al, J Immunol 1988, 140: 4294 ; Takematsu et al, Arch Dermatol 1993, 129: 74 ; Liu et al, 1997, 100:1256; Jeffery, Thorax 1998, 53: 129 ; Pesci et al, Eur Respir J.
  • PMN Polymorphonuclear Neutrophils
  • IL-8 The biological activity of IL-8 is mediated by the interaction with two receptors, CXCR1 and CXCR2, belonging to the 7TM-GPCR family, that are expressed on the surface of human PMNs.
  • CXCR1 is selective, binding with high affinity only two chemokines, CXCL6 and IL-8, and showing a much higher affinity for IL-8 ( Wolf et al, Eur J Immunol 1998, 28: 164 )
  • human CXCR2 is a more promiscuous receptor, binding a number of different cytokines and chemokines. Therefore, CXCR2 mediates the activity of a number of different biological molecules.
  • Interleukin-6 is a pleiotropic cytokine with multiple functions in immune regulation, inflammation, and oncogenesis. Binding of IL-6 to the IL-6 receptor (IL-6R) induces homodimerization and recruitment of glycoprotein 130 (gp130), which leads to activation of downstream signaling.
  • IL-6R IL-6 receptor
  • Gp130 is part of the receptor signaling complexes for at least 8 cytokines (IL-6, IL-11, IL-27, LIF, CNTF, OSM, CT-1, and CLC). Ligand binding induces the association of gp130 with a cytokine-specific receptor-a chain, followed by the activation of downstream signaling cascades including JAK/STAT, RAS/RAF/MAPK, and PI3K/AKT pathways. It has been shown that phosphorylation of gp130 at Ser782 downregulates cell surface expression of gp130. As a ubiquitously expressed receptor, gp130 is involved in a wide range of important biologic processes including inflammation, autoimmunity, cancer, stemcell maintenance, and embryonic development ( Mol Cancer Ther; 12(6); 937-49; 2013 ).
  • cytokines IL-6, IL-11, IL-27, LIF, CNTF, OSM, CT-1, and CLC.
  • the present inventors have surprisingly found that inhibition of IL-8 is able to reduce or prevent the occurrence of lung metastasis associated with osteosarcoma, Ewing sarcoma or rhabdomyosarcoma.
  • the combination of an IL-8 inhibitor with an IL-6 inhibitor is resulted more effective.
  • an IL-8 inhibitor is useful in the prevention and/or treatment of the primary tumor osteosarcoma, Ewing sarcoma or rhabdomyosarcoma.
  • IL-8 inhibitor is combined with a chemotherapeutic agent.
  • a first object of the present invention is a product or kit for use in the prevention and/or treatment of lung metastasis associated to osteosarcoma, the product or kit comprising: A) an IL-8 inhibitor, and B) at least one IL-6 inhibitor and/or at least one gp130 inhibitor, A) and B) being two separate formulations for simultaneous, separate or sequential use.
  • the second object of the invention is a pharmaceutical composition for use in the prevention and/or treatment of lung metastasis associated to osteosarcoma, comprising an IL-8 inhibitor and pharmaceutically acceptable excipients and/or diluents, wherein the pharmaceutical composition further comprises at least one IL-6 inhibitor and/or at least one gp130 inhibitor.
  • the present inventors have found that molecules acting as inhibitors of IL-8 activity have therapeutic efficacy in animal models of sarcoma. Furthermore, the present inventors have also found that IL-8 inhibition is able to counteract the onset of lung metastasis. In particular, the combined IL-8 and IL-6 inhibition prevents metastasis.
  • a first object of the present invention is a product or kit for use in the prevention and/or treatment of lung metastasis associated to osteosarcoma, the product or kit comprising: A) an IL-8 inhibitor, and B) at least one IL-6 inhibitor and/or at least one gp130 inhibitor, A) and B) being two separate formulations for simultaneous, separate or sequential use.
  • IL-8-inhibitor refers to any compound able to inhibit, partially or totally, the biological activity of IL-8. Such a compound can act by decreasing the expression or activity of IL-8 or by inhibiting the triggering of the intracellular signaling activated by the IL-8 receptors. It is preferred that said IL-8 inhibitor is able to inhibit at least 50%, preferably at least 60%, of the chemotaxis induced by IL-8 in PMNs at a concentration equal or below 500 nM, preferably below 100nM.
  • the IL-8 inhibitor of all the objects of the present invention inhibits the activity of IL-8 mediated by CXCR1 receptor or mediated by both CXCR1 and CXCR2 receptors.
  • said IL-8 inhibitor is either an allosteric inhibitor or an orthosteric antagonist of CXCR1 receptor or of both CXCR1 and CXCR2 receptors.
  • said IL-8 inhibitor is selective for CXCR1 receptor or is equally potent towards CXCR1 and CXCR2 receptors.
  • selective for CXCR1 it is meant a compound that shows an IC 50 value at least 2, preferably 3, logs higher toward CXCR1 than towards CXCR2. ( Bertini R. et al., Proc. Nat. Acad. Sci. USA (2004), 101 (32), pp. 11791-11796 ).
  • the IL-8 inhibitor according to the invention has an IC 50 value towards CXCR1 receptor in the low nanomolar range, preferably in the range 0.02-5 nanomolar.
  • said IL-8 inhibitor is selected from small molecular weight molecules and antibodies, more preferably it is a small molecular weight molecule.
  • IL-8 inhibitors according to the above definition, able to inhibit the activity of IL-8 mediated by CXCR1 receptor or mediated by both CXCR1 and CXCR2 receptors, are known in the art.
  • Preferred IL-8 inhibitors according to the invention are selected from 1,3-thiazol-2-ylaminophenylpropionic acid derivatives, 2-phenyl-propionic acid derivatives and their pharmaceutically acceptable salts.
  • said 1,3-thiazol-2-ylaminophenylpropionic acid derivative is preferably a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein
  • these compounds X is OH.
  • Y is a heteroatom selected from S, O and N; preferably it is S.
  • Z is selected from linear or branched C 1 -C 4 alkyl, linear or branched C 1 -C 4 alkoxy, halo C 1 -C 3 alkyl and halo C 1 -C 3 alkoxy; preferably it is selected from methyl, methoxy, trifluoromethoxy, trifluoromethyl, more preferably it is trifluoromethyl.
  • the chiral carbon atom of the phenylpropionic group is in the S configuration.
  • WO2010/031835 discloses their method of synthesis, their activity as IL-8 inhibitors as well as their use in the treatment of IL-8 dependent pathologies such as transient cerebral ischemia, bullous pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and damages caused by ischemia and reperfusion.
  • said 2-phenyl-propionic acid derivative is preferably a compound of formula (II):
  • R 5 is H or linear or branched C 1 -C 3 alkyl, preferably it is H.
  • R 6 is linear or branched C 1 -C 6 alkyl or trifluoromethyl; preferably, it is a linear or branched C 1 -C 6 alkyl, more preferably it is CH 3 .
  • R 4 is C 1 -C 6 alkyl or benzoyl; preferably it is in positions 3 and 4, more preferably, it is 3-benzoyl or 4-isobutyl.
  • R 5 is H or linear or branched C 1 -C 3 alkyl, preferably it is H, R 6 is linear or branched C 1 -C 6 alkyl or trifluormethyl; preferably it is a linear or branched C 1 -C 6 alkyl, more preferably it is CH 3 .
  • the chiral carbon atom of the phenylpropionic group is in the R configuration.
  • Particularly preferred compounds of formula (II) according to the invention are selected from R-(-)-2-(4-isobutylphenyl)propionyl methansulfonamide (also known as Reparixin) and pharmaceutically acceptable salts thereof.
  • said compound is the lysine in situ salt of R(-)-2-(4-isobutylphenyl)propionyl methansulfonamide (herein indicated also as DF1681B).
  • compounds of formula (II) or (III) according to the invention are 2-(4-trifluoromethanesulfonyloxy)phenyl]-N-methanesulfonyl propionamide and pharmaceutically salts thereof, preferably its sodium salt preferably R(-)-2-(4-trifluoromethanesulfonyloxy)phenyl]-N-methanesulfonyl propionamide (also known as DF2156Y) and its sodium salt (also known as Ladarixin or DF2156A).
  • IL-8 inhibitors of formula (II) and (III) are disclosed in WO0024710 and WO2005/090295 , that also disclose their method of synthesis, their activity as IL-8 inhibitors as well as their use as inhibitors of neutrophils chemotaxis and degranulation induced by IL-8 and in the treatment of IL-8 dependent pathologies such as psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary diseases (COPD), bullous pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and damages caused by ischemia and reperfusion.
  • COPD chronic obstructive pulmonary diseases
  • a "therapeutically effective amount” refers to an amount sufficient to achieve treatment or prevention of the disease. Determination of the effective amounts is well within the capability of those skilled in the art based upon the achievement of a desired effect. An effective amount will depend on factors including, but not limited to, the weight of a subject and/or the degree of the disease or unwanted condition from which a subject suffers.
  • treatment refers to the eradication/amelioration or prevention/delay in onset, respectively, of the disorder being treated or of one or more of the symptoms associated thereof, notwithstanding the fact that the patient may still be afflicted with the underlying disorder.
  • the second object of the present invention is a pharmaceutical composition for use in the prevention and/or treatment of lung metastasis associated to osteosarcoma, comprising an IL-8 inhibitor and pharmaceutically acceptable excipients and/or diluents, wherein the pharmaceutical composition further comprises at least one IL-6 inhibitor and/or at least one gp130 inhibitor.
  • IL-6 inhibitor refers to any compound able to inhibit, partially or totally, the biological activity of IL-6.
  • gp130 inhibitor refers to any compound able to inhibit, partially or totally, the biological activity of gp130.
  • said pharmaceutical composition for the prevention and/or treatment of lung metastasis associated to osteosarcoma further comprises at least one chemotherapeutic agent.
  • said gp130 inhibitor is selected from the group comprising 2-(7-Fluoropyrrolo[1,2-a]quinoxalin-4-yl) 2-pyrazinecarboxylic acid hydrazide (SC144), Raloxifene and (4R)-3-((2S,3S)-3-hydroxy-2-methyl-4-methylenenonanoyl)-4-isopropyldihydrofuran-2(3H)-one (LMT-28) ( Tae-Hwe Heo et al.; Oncotarget, Vol. 7, No. 13, 15460- 15473; 2016 ).
  • said IL-6 inhibitor is selected from the group comprising SC144, Vobarilizumab, Siltuximab, Sirukumab, Olokizumab, Clazakizumab, MAb 1339, Tocilizumab and Sarilumab ( Tae-Hwe Heo et al.; Oncotarget, Vol. 7, No. 13, 15460- 15473; 2016 ).
  • said IL-6 inhibitor is SC144.
  • the inhibitors of IL-8 according to the present invention are formulated in pharmaceutical compositions suitable for use by oral formulation, such as tablets, capsules, syrups, preferably in the form of controlled release formulations, or by parenteral administration, preferably in the form of sterile solutions suitable for intravenous or intramuscular administration.
  • oral formulation such as tablets, capsules, syrups
  • parenteral administration preferably in the form of sterile solutions suitable for intravenous or intramuscular administration.
  • the pharmaceutical compositions can be prepared according to conventional methods, for example as disclosed in Remington, "The Science and Practice of Pharmacy", 21st ed. (Lippincott Williams and Wilkins ).
  • the average daily dose depends on several factors such as the severity of the disease, the condition, age, sex and weight of the patient.
  • the dose will vary generally from 1 to 1500 mg of compounds of formula (I) per day optionally divided in multiple administrations.
  • OS-17 was derived from the OS-17 xenograft and obtained from the Istituti Ortopedici Rizzoli, Bologna, Italy.
  • OS-25 and OHS were a gift from Dr. Fodstad's lab at the Radium Hospital in Oslo. All were maintained in RPMI (Corning #10-040-CV) supplemented with 10% FBS (Atlanta Biologicals #S11150H).
  • FBS Antlanta Biologicals #S11150H
  • 143B and K7M2 cells were obtained from ATCC (ATCC #CRL ⁇ 8303 and #CRL2836) and grown in DMEM (Corning #10-013-CV) supplemented with 10% FBS.
  • OSCA-8 and OSCA-16 were provided by Jamie Modiano and the University of Minnesota and grown in RPMI with 10% FBS.
  • Lung smooth muscle cells (ATCC #PCS-130-10) were grown in vascular cell basal medium (ATCC #PCS-100-030) supplemented with the vascular smooth muscle cell growth kit (ATCC #PCS-100-042).
  • HUVEC cells (Lonza CC-2517) were grown in endothelial basal medium (Lonza #CC-5036) supplemented with the EGM-plus single quote (Lonza #CC-4542).
  • Human lung fibroblasts (ATCC #PCS-201-013) were grown in EMEM (ATCC #30-2003) supplemented with 10% FBS.
  • HBEC3-KT cells (ATCC #CRL-4051) were grown in airway epithelial cell basal medium (ATCC #PCS-300-030) supplemented with the bronchial epithelial cell growth kit (ATCC #PCS-300-040).
  • Macrophages were derived from monocytes isolated from whole blood (obtained through an institutional IRB-approved protocol for the procurement of fresh human blood) using a CD14 magnetic bead selection system (Miltenyi #130-050-201) followed by 72 hours of culture in XVIVO serum-free medium (Lonza #04-380Q) supplemented daily with 20 ng/ml of recombinant human M-CSF (BioLegend #574802).
  • cultures within each group co-culture and related monocultures were performed using a 1:1 mixture of the two corresponding growth media to control for differences in media components.
  • IL-6 and IL-8 ELISA Cell-free supernatants from 72-hour cultures of each cell line performed in 24-well plates were evaluated for IL-6 and IL-8 concentrations using R&D DuoSet ELISA Development Kits (#DY206 and #DY208), used according to manufacturer recommendations.
  • Transwell migration and invasion assays 1 ⁇ 10 4 OS cells were plated into transwell inserts (either Falcon #353097 for migration or Corning #354483 for Matrigel invasion assays) containing appropriate chemotactic factors. After 24 hours of incubation, transwells were drained and upper chambers/membrane upper surfaces scraped using a polyester swab. Membranes were stained using a Dif-Quik Stain Set (Siemens #B4132-1A) and dried, then imaged on an inverted microscope. Cells were quantified using Adobe Photoshop counting tools.
  • media contained 1% FBS in both chambers, with recombinant protein added to the bottom chamber to make 50 ng/ml IL6 (BioLegend #570804) or 100 ng/ml IL-8 (BioLegend #574204).
  • top chambers contained RPMI only, while bottom chambers contained 1% or 2.5% serum.
  • 20 ug/ml of neutralizing antibodies to either IL6 (Abcam #AB6672), IL-8 (Abcam #AB18672), or both were added to both upper and lower chambers.
  • OS cell proliferation Cells plated at 20% confluence were cultured in growth medium as above containing inhibitors as noted in each figure. Proliferation was serially quantified using an Essen Biosciences Incucyte Zoom over the time period noted in each figure.
  • CB17-SCID mice inoculated via tail vein with 1 ⁇ 10 6 OS-17 cells (day 0) received daily injections of sc144 (10 mg/kg SC once daily, Sigma #SML0763), DF2156A (30 mg/kg IP once daily), or both beginning 24 hours after inoculation.
  • sc144 was prepared by dissolving with warming in DMSO to make a 40 mg/kg solution, which was immediately diluted to 2 mg/kg using 40% propylene glycol/1% Tween-20 in water. An average 20 g mouse received 100 ul per dose. Doses of sc144 were prepared fresh each day.
  • DF2156A was prepared by dissolving in PBS to create a 6 mg/ml solution for similar 100 ul doses in a 20 g mouse. Treatments continued for 42 days, then stopped. Mice were monitored with twice weekly weights and enhanced body condition scoring (eBCS (28)). Mice demonstrating >10% weight loss or eBCS ⁇ 8 were euthanized and tissues harvested, lungs insufflated, fixed in 10% neutral buffered formalin, then embedded and processed as above. Mice not demonstrating metastatic disease burden (presumably dying from other causes) are censored in the survival analysis. This includes 2 mice receiving combined therapy, one receiving sc144, and one control mouse.
  • eBCS enhanced body condition scoring
  • mice 6-8 week old CB17-SCID mice were inoculated with 1 ⁇ 10 6 143B, OSCA-8, OSCA-16, or K7M2 cells (for K7M2 cells, immunocompetent Balb/c mice were used). 24 hours after inoculation, mice began treatment with daily sc144 and/or DF2156A, which continued for 42 days as above. Mice were then observed as above until one mouse from any given cell line group reached endpoint. If lungs taken from this sentinel mouse showed signs of metastatic disease, all mice from that group were euthanized, lungs harvested, insufflated, fixed, embedded, and stained.
  • the present inventors tested a panel of osteosarcoma cell lines for their ability to colonize mouse lung.
  • the present inventors found that OS-17 cells, when introduced into circulation via tail vein, develop metastatic loci with very high efficiency, while OHS cell lines demonstrate much lower metastatic efficiency ( Figure 1 ). This effect remained consistent across multiple passages of cells and multiple assays.
  • the present inventors tested these cell lines for production of IL-6 and IL-8 by subjecting cell-free supernatants to ELISA ( Figure 1d ), which revealed a strong correlation between tumor cell production of both of these cytokines and the cell line's capacity to colonize murine lung.
  • IL-6 and IL-8 stimulate chemokinesis and directional migration in OS cells, regardless of metastatic potential
  • mice inoculated via tail vein with 1 ⁇ 10 6 luciferase-labeled OS-17 cells received treatment with sc144 (the gp130 inhibitor), DF2156A (the CXCR1/2 inhibitor), or both. Mice continued to receive treatment for 42 days, after which treatment stopped.
  • Intravital imaging for in vivo assessment of tumor burden was performed at 14 and 24 days using standard bioluminescent techniques. Bioluminescent imaging suggested markedly decreased tumor burden in the lungs of mice receiving combined therapy relative to those receiving no treatment or single-agent therapy ( Figure 3 A) .
  • mice from each single-agent treatment group were euthanized 24 hours after the 14 th dose of drug to perform pharmacodynamics (PD) assessment of target inhibition.
  • Lungs from those mice stained with IHC for either pFAK (DF2156A) or pSTAT3 (gp130) showed sustained target inhibition (i.e. sustained drug activity) at dosing trough ( Figure 4 ).
  • mice Following treatment, mice were then observed until demonstrating signs of clinical deterioration, either weight loss >10% or enhanced body condition score (eBCS) ⁇ 8, our defined endpoints.
  • eBCS enhanced body condition score
  • mice were euthanized using approved methods and lungs were harvested, insufflated, fixed, embedded, sectioned, and stained.
  • the present inventors repeated the treatment-related experiments using a number of different models. These included a syngeneic, immunocompetent model using a cell line derived from a spontaneously-arising OS in a Balb/c mouse (K7M2), xenograft models of canine OS (OSCA-8 and OSCA-16), and additional xenograft models of human OS (143B). Mice inoculated with tumor cells were treated with either no drug or combined sc144 and DF2156A for 42 days.

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Claims (14)

  1. Produkt oder Kit zur Verwendung bei der Vorbeugung und/oder Behandlung von Lungenmetastasen im Zusammenhang mit Osteosarkomen, wobei das Produkt oder Kit umfasst:
    A) einen IL-8-Inhibitor und
    B) mindestens einen IL-6-Inhibitor und/oder mindestens einen gp130-Inhibitor,
    wobei A) und B) zwei getrennte Formulierungen zur gleichzeitigen, getrennten oder aufeinanderfolgenden Verwendung sind.
  2. Produkt oder Kit zur Verwendung nach Anspruch 1, wobei der IL-8-Inhibitor eine Verbindung der Formel (I) ist,
    Figure imgb0008
     wobei
    - R1 Wasserstoff oder CH3 ist;
    - R2 Wasserstoff oder lineares C1-C4-Alkyl ist, vorzugsweise ist es Wasserstoff;
    - Y ein Heteroatom ist, ausgewählt aus S, O und N; vorzugsweise ist es S;
    - Z aus Halogen, linearem oder verzweigtem C1-C4-Alkyl, C2-C4-Alkenyl, C2-C4-Alkinyl, C1-C4-Alkoxy, Hydroxyl, Carboxyl, C1-C4-Acyloxy, Phenoxy, Cyano, Nitro, Amino, C1-C4-Acylamino, Halogen-C1-C3-Alkyl, Halogen-C1-C3-Alkoxy, Benzoyl, linearem oder verzweigtem C1-C8-Alkansulfonat, linearem oder verzweigtem C1-C8-Alkansulfonamid, linearem oder verzweigtem C1-C8-Alkylsulfonylmethyl ausgewählt ist; vorzugsweise ist es Trifluormethyl;
    - X OH oder ein Rest der Formel NHR3 ist; wobei R3 ausgewählt ist aus:
    - Wasserstoff, Hydroxyl, linearem oder verzweigtem C1-C6-Alkyl, C3-C6-Cycloalkyl, C2-C6-Alkenyl, C1-C5-Alkoxy,
    oder C1-C6-Phenylalkyl, wobei die Alkyl-, Cycloalkyl- oder Alkenylgruppe durch einen COOH-Rest substituiert werden kann,
    - einen Rest der Formel SO2R4, wobei R4 C1-C2-Alkyl, C3-C6 -Cycloalkyl, C1-C3-Halogenalkyl ist.
  3. Produkt oder der Kit zur Verwendung nach Anspruch 2, wobei in dem IL-8-Inhibitor der Formel (I):
    R1 Wasserstoff oder CH3 ist;
    X OH ist;
    R2 Wasserstoff oder lineares C1-C4-Alkyl ist,
    Y ein Heteroatom ist, ausgewählt aus S, O und N;
    Z aus linearem oder verzweigtem C1-C4-Alkyl, linearem oder verzweigtem C1-C4-Alkoxy, Halogen-C1-C3-Alkyl und Halogen-C1-C3-Alkoxy ausgewählt ist.
  4. Produkt oder Kit zur Verwendung nach Anspruch 2, wobei in dem IL-8-Inhibitor der Formel (I) R1 Wasserstoff ist und das chirale Kohlenstoffatom der Phenylproprionsäuregruppe in der S-Konfiguration vorliegt.
  5. Produkt oder Kit zur Verwendung nach Anspruch 2 oder 3, wobei der IL-8-Inhibitor der Formel (I) aus 2-Methyl-2-(4-{[4-(trifluormethyl)-1,3-thiazol-2-yl]amino}-phenyl)-propansäure und pharmazeutisch annehmbaren Salzen davon, vorzugsweise seinem Natriumsalz und (2S)-2-(4-{[4-(Trifluormethyl)-1,3-thiazol-2-yl]amino}-phenyl)-propansäure und pharmazeutisch annehmbaren Salzen davon, vorzugsweise seinem Natriumsalz ausgewählt ist.
  6. Produkt oder Kit zur Verwendung nach Anspruch 1, wobei der IL-8-Inhibitor eine Verbindung der Formel (II),
    Figure imgb0009
    oder ein pharmazeutisch annehmbares Salz davon ist,
    wobei:
    R4 lineares oder verzweigtes C1-C6-Alkyl, Benzoyl, Phenoxy, Trifluormethansulfonyloxy ist; vorzugsweise ist es aus Benzoyl, Isobutyl und Trifluormethansulfonyloxy ausgewählt;
    R5 H oder lineares oder verzweigtes C1-C3-Alkyl ist, vorzugsweise ist es H;
    R6 lineares oder verzweigtes C1-C6-Alkyl oder Trifluormethyl ist; vorzugsweise ist es ein lineares oder verzweigtes C1-C6-Alkyl, bevorzugter ist es CH3.
  7. Produkt oder Kit zur Verwendung nach Anspruch 6, wobei R4 in Position 3 oder 4 am Phenylring ist, bevorzugter ist es 3-Benzoyl, 4-Isobutyl oder 4-Trifluormethansulfonyloxy.
  8. Produkt oder Kit zur Verwendung nach Anspruch 1, wobei der IL-8-Inhibitor eine Verbindung der Formel (III),
    Figure imgb0010
    oder ein pharmazeutisch annehmbares Salz davon ist,
    wobei
    R' Wasserstoff ist;
    R ein Rest der Formel SO2Ra ist, wobei Ra lineares oder verzweigtes C1-C4-Alkyl oder Halogen-C1-C3-Alkyl ist, vorzugsweise ist es CH3.
  9. Produkt oder Kit zur Verwendung nach Anspruch 6, wobei in dem IL-8-Inhibitor der Formel (II) das chirale Kohlenstoffatom der Phenylpropionsäuregruppe in der R-Konfiguration vorliegt.
  10. Produkt oder Kit zur Verwendung nach Anspruch 6, wobei der IL-8-Inhibitor der Formel (II) aus R-(-)-2-(4-Isobutylphenyl)propionylmethansulfonamid und pharmazeutisch akzeptablen Salzen davon, vorzugsweise dem Lysin in situ-Salz ausgewählt ist.
  11. Produkt oder Kit zur Verwendung nach einem der Ansprüche 6 bis 9, wobei der IL-8-Inhibitor R(-)-2-(4-Trifluormethansulfonyloxy)phenyl]-N-methansulfonylpropionamid und pharmazeutisch akzeptable Salze davon, vorzugsweise seinem Natriumsalz, ist.
  12. Produkt oder Kit zur Verwendung nach Anspruch 1, wobei der mindestens eine gp130-Inhibitor aus der Gruppe ausgewählt ist, die 2-(7-Fluorpyrrolo[1,2-a]chinoxalin-4-yl)-2-pyrazincarbonsäurehydrazid, Raloxifen und (4R)-3-((2S,3S)-3-Hydroxy-2-methyl-4-methylenenonanoyl)-4-isopropyldihydrofuran-2(3H)-on umfasst.
  13. Produkt oder Kit zur Verwendung nach Anspruch 1, wobei der mindestens eine IL-6-Inhibitor aus der Gruppe ausgewählt ist, die SC144, Vobarilizumab, Siltuximab, Sirukumab, Olokizumab, Clazakizumab, MAb 1339, Tocilizumab und Sarilumab umfasst.
  14. Pharmazeutische Zusammensetzung zur Verwendung bei der Vorbeugung und/oder Behandlung von Lungenmetastasen im Zusammenhang mit Osteosarkomen, umfassend einen IL-8-Inhibitor und pharmazeutisch annehmbare Hilfsstoffe und/oder Verdünnungsmittel, wobei die pharmazeutische Zusammensetzung ferner mindestens einen IL-6-Inhibitor und/oder mindestens einen gp130-Inhibitor umfasst.
EP18795414.4A 2017-10-24 2018-10-23 Kombination von il-8-inhibitoren und il-6/gp-130-inhibitoren zur behandlung von lungenmetastasen in verbindung mit osteosarkomen Active EP3700514B1 (de)

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SM20250202T SMT202500202T1 (it) 2017-10-24 2018-10-23 Combinazione di inibitori di il-8 e inibitori di il-6/gp-130 per uso nel trattamento di metastasi polmonari associate all'osteosarcoma
SI201831238T SI3700514T1 (sl) 2017-10-24 2018-10-23 Kombinacija zaviralcev il-8 in zaviralcev il-6/gp-130 za uporabo pri zdravljenju pljučnih metastaz, povezanih z osteosarkomom
RS20250531A RS66852B1 (sr) 2017-10-24 2018-10-23 Kombinacija inhibitora il-8 i inhibitora il-6/gp-130 za primenu u lečenju plućnih metastaza udruženih sa osteosarkomom
HRP20250641TT HRP20250641T1 (hr) 2017-10-24 2018-10-23 Kombinacija inhibitora il-8 i inhibitora il-6/gp-130 za primjenu u liječenju plućnih metastaza udruženih s osteosarkomom

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